Total pancreatectomy with islet autotransplantation (TP-IAT) is currently being performed to treat intractable pain and to prevent brittle diabetes in well-selected patients with chronic pancreatitis. A major problem associated with TP-IAT is that the number of islets available for transplantation is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis immediately after intraportal infusion when transplantation-associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines, etc.) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality of life are significantly improved in our TP-IAT patients, ony 25% of them become insulin independent (compared to >85% pre-operatively), 19% require minimal insulin (<10u/day) replacement and the rest develop pancreatogenic diabetes after surgery. Strategies that produce islets more robust to resist stressors that induce cell apoptosis are extremely appealing to prevent onset of surgical diabetes and to improve the efficiency of human islet auto-transplantation. We have been focused on exploring strategies that can prevent islet cell death after allogeneic transplantation to treat patient with type 1 diabetes over the past 10 years. Our data indicate that induction of a protective gene, heme oxygenase-1 (HO-1), or exposing the product of HO-1 enzymatic activity, carbon monoxide (CO), protects islet allografts from immune rejection after transplantation. HO-1 gene expression was dramatically reduced in islets from chronic pancreatitis patient compared to those from healthy individual and HO-1 induction protects islets from hypoxia-induced cell death. Moreover, encapsulating islets with biodegradable poly-lactic-co-glycolic acid (PLGA) nanoparticles also protect islets from apoptosis in a murine islet transplantation model. We hypothesize that induction of HO-1/CO exposure, in combination with islet encapsulation, can make human islets more resistant to injuries and lead to better survival after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. In this proposal, we aim to develop a novel HO-1/CO-based islet encapsulation protocol that can make islets more resistant to injuries encountered during isolation and after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. Our strong research team that includes islet transplantation biologists, islet transplantation surgeons, endocrinologists and bioengineering experts, and our state-of-the-art cGMP facility at MUSC offers a convenient and powerful platform that can facilitate the translation of our research findings from bench to bedside.